Antipsychotic
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of iloperidone in human pregnancy have been located. Animal reproduction studies observed two types of developmental toxicity (death and decreased weight) in one animal species. There is no evidence with other agents in this subclass of embryo or fetal harm. However, because of the very limited human pregnancy experience with atypical antipsychotics, the American College of Obstetricians and Gynecologists does not recommend the routine use of these agents in pregnancy, but a risk–benefit assessment may indicate that such use is appropriate (1). Because iloperidone is indicated for severe debilitating mental disease, the benefits to the mother appear to outweigh the unknown risk. A 1996 review on the management of psychiatric illness concluded that patients with histories of chronic psychosis represent a high-risk group (for both the mother and the fetus) and should be maintained on pharmacologic therapy before and during pregnancy (2). Folic acid 4 mg/day has been recommended for women taking atypical antipsychotics because they may have a higher risk of neural tube defects due to inadequate folate intake and obesity (3).
FETAL RISK SUMMARY
The atypical antipsychotic iloperidone is a benzisoxazole derivative in the same subclass of antipsychotic agents as paliperidone, risperidone, and ziprasidone. Iloperidone is indicated for the acute treatment of schizophrenia in adults. It is extensively metabolized to two predominate metabolites, P88 and P95, one (P88) of which is active. The parent drug and the two metabolites are highly bound (about 95%) to serum proteins. The mean elimination half-lives of iloperidone and the two metabolites (P88 and P95) in extensive metabolizers were 18, 26, and 23 hours, respectively, whereas in poor metabolizers the half-lives were 33, 37, and 31 hours, respectively (4).
Reproduction studies have been conducted in rats and rabbits. During organogenesis, rats were given doses 1.6–26 times the maximum recommended human dose of 24 mg/day based on BSA (MRHD). The highest dose caused increased early intrauterine deaths, decreased fetal weight and length, decreased skeletal ossification, and an increased incidence of minor fetal skeletal anomalies and variations and also was maternal toxic (decreased food consumption and weight gain). In separate studies, rats were given doses 1.6–26 times the MRHD either before conception or from gestational day 17 through weaning. Adverse effects included prolonged pregnancy and parturition, increased stillbirth rates, increased incidence of fetal visceral variations, decreased fetal and pup weights, and decreased postpartum pup survival. Maternal toxicity occurred at the higher doses. An increase in stillbirths occurred at all doses. The no-effect dose for the other effects ranged from 1.6 to about 5 times the MRHD. No drug effects on neurobehavioral or reproductive development were noted in the surviving pups. In rabbits during organogenesis, the highest dose tested (20 times the MRHD) was not teratogenic but did cause increased early intrauterine deaths, decreased fetal viability at term, and maternal toxicity (4).
Because P95 is not present in significant amounts in rats, a separate study was conducted in this species with the metabolite. During organogenesis, doses resulting in plasma levels up to twice those in humans receiving the MRHD did not cause teratogenicity, but delayed skeletal ossification occurred at all doses. No significant maternal toxicity was noted (4).
Long-term studies for carcinogenicity have been conducted in mice and rats. An increased incidence of malignant mammary gland tumors occurred in female mice that were considered to be prolactin mediated. No drug-related carcinogenicity was observed in rats. Long-term exposure to the P95 metabolite in rats resulted in proliferative responses in several organs. Neither iloperidone nor P95 was mutagenic in various assays, but the parent drug did cause chromosomal aberrations in one in vitro assay that also resulted in cytotoxicity. Decreased fertility in male and females was observed at doses >≈5 times the MRHD. The no-effect dose for impaired fertility was 1.6 times the MRHD (4).
It is not known if iloperidone or the two metabolites cross the human placenta. The molecular weight of the parent drug (about 426) and the long elimination half-lives suggest that the parent drug and possibly the metabolites will cross to the embryo–fetus. The high serum protein binding of iloperidone might limit some of this exposure.
BREASTFEEDING SUMMARY
No reports describing the use of iloperidone during human lactation have been located. The molecular weight (about 426) and the long elimination half-lives (ranging from 18–36 hours) suggest that the drug will be excreted into breast milk. However, there are two major metabolites, one of which is active, and these may also be excreted into milk. The amount of iloperidone and metabolites in milk might be limited by their high (about 95%) serum protein binding. The effect of this exposure on a nursing infant is unknown.
The manufacturer recommends women receiving iloperidone should not breastfeed (4). Moreover, the American Academy of Pediatrics classifies other atypical antipsychotics (e.g., see Ziprasidone) as drugs whose effect on the nursing infant is unknown but may be of concern (5).
Because of the very limited human experience with atypical antipsychotics, the American College of Obstetricians and Gynecologists does not recommend the routine use of these agents during lactation, but a risk–benefit assessment may indicate that such use is appropriate (1).
References
1.American College of Obstetricians and Gynecologists. Use of psychiatric medications during pregnancy and lactation. ACOG Practice Bulletin. No. 92, April 2008. Obstet Gynecol 2008;111:1001–19.
2.Althuler LL, Cohen L, Szuba MP, Burt VK, Gitlin M, Mintz J. Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines. Am J Psychiatry 1996;153:592–606.
3.Koren G, Cohn T, Chitayat D, Kapur B, Remington G, Myles-Reid D, Zipursky RB. Use of atypical antipsychotics during pregnancy and the risk of neural tube defects in infants. Am J Psychiatry 2002;159:136–7.
4.Product information. Fanapt. Vanda Pharmaceuticals, 2009.
5.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.